Despite intensive search for schizophrenia susceptibility genes, the genetic basis of this devastating mental illness remains elusive. Newly emerging evidence suggests that rare genetic mutations that disrupt neurodevelopmental pathways may play a larger role in the illness than was previously believed. Thus, a complementary strategy that may provide valuable insights into the pathogenesis of schizophrenia is the study of a disorder with known genetic etiology that shares its phenotypic characteristics. The 22q11.2 deletion syndrome (Velocardiofacial/ DiGeorge syndrome; 22qDS) is a compelling model, as it represents the most common known genetic risk factor for the development of psychotic illness. Because 22qDS has a known genetic etiology and consistent neurobehavioral phenotype, investigation of this syndrome offers an extraordinary opportunity for narrowing the search among possible neuroanatomic and genetic mechanisms underlying the development of psychotic symptoms in adolescence. Here we propose to conduct 2-year longitudinal investigations (over a 5-year funding period) of a large cohort of children and adolescents with 22qDS and demographically comparable healthy controls. We will apply dimensional measures of psychopathology, neurocognitive assays, and novel brain imaging methods, in order to elucidate risk factors for emergence of psychotic symptoms during adolecence in youth with this syndrome. In particular, we will test the hypotheses that more severe structural brain anomalies at baseline, as well as progressive worsening over time, are predictive of symptom severity in 22qDS, consistent with the theoretical involvement of deviant adolescent neuromaturational processes in psychotic symptom development. These differences will be examined in relation to variability in deletion size and to hemizygous allelic variability in neurodevelopmental genes within the 22q11.2 locus. This work will establish the neural substrates for the neurobehavioral phenotypes seen in 22qDS, and advance our understanding of the genetic and developmental mechanisms by which haploinsufficiency at 22q11.2 compromises brain structure and function. PUBLIC HEALTH RELEVANCE: Chromosomal deletions at 22q11.2 represent the highest known genetic risk factor for development of psychotic illness. Here we will prospectively study the links between genetic variation, brain structure, and behavior in children with 22q11.2 deletions, in order to advance our understanding of the mechanisms underlying the development of psychotic symptoms during adolescence in this syndrome. These findings will also shed light on genetic influences on brain development and psychosis in the broader population.